Rifabutin treatment methods, uses, and compositions
Inventors
Dale, Glenn E. • Lociuro, Sergio • Gitzinger, Marc • Biondi, Stefano • BOUROTTE, Marilyne
Assignees
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Publication Number
US-11903934-B2
Publication Date
2024-02-20
Expiration Date
Abstract
The invention provides formulations containing highly concentrated solutions of rifabutin and methods of making such formulations. The invention also provides methods of using such formulations to treat a bacterial infection in a subject.
Core Innovation
The disclosed subject matter provides a rifabutin formulation comprising a solution of rifabutin in aqueous solution, where the solution includes a solvent, water, and an acid. The rifabutin is present at a concentration between about 50 mg/mL and about 250 mg/mL, and the formulation is characterized as highly concentrated and reconstituted.
A central aspect is the use of an acid together with a solvent and water to promote rapid dissolution of rifabutin powder and to maintain rifabutin solubility upon dilution. Exemplary acid/solvent combinations include DMI or transcutol HP with acetic acid or D-glucuronic acid, and the document also describes hydrochloric acid, methanesulfonic acid, phosphoric acid, L-tartaric acid, L-malic acid, D-gluconic acid, L-lactic acid, and L-aspartic acid.
The concentrated rifabutin aqueous solutions can be diluted using specified diluents without precipitation and can be used for non-oral administration such as IV or inhalation. The formulation content includes specific solvent components including DMI, transcutol HP, Tween 80, Tween 20, PEG, propylene glycol, NMP, glycerin, ethanol, and DMA.
Claims Coverage
The independent claim covers a rifabutin aqueous solution formulation with solvent, water, and acid enabling high-concentration aqueous rifabutin between about 50 mg/mL and about 250 mg/mL. Dependent claims further refine the formulation by selecting specific solvents and acids, by specifying the rifabutin form as a pharmaceutically acceptable salt, and by selecting a presentation such as an IV bag.
A solvent, water, an acid, and rifabutin in aqueous solution at a defined concentration
A solution comprising a solvent, water, an acid, and rifabutin in aqueous solution at a concentration between about 50 mg/mL and about 250 mg/mL.
A solvent selected from specified solvents
The rifabutin formulation uses a solvent selected from polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polyethylene glycol (PEG), propylene glycol, N-methyl-2-pyrrolidone (NMP), glycerin, ethanol, dimethylacetamide (DMA), diethylene glycol monoethyl ether (transcutol HP), and dimethyl isosorbide (DMI).
An acid selected from specified acids
The rifabutin formulation has an acid selected from hydrochloric acid, methanesulfonic acid, phosphoric acid, L-tartaric acid, D-glucuronic acid, L-malic acid, D-gluconic acid, L-lactic acid, acetic acid, and L-aspartic acid.
Rifabutin as a pharmaceutically acceptable salt
The formulation includes rifabutin in the form of a pharmaceutically acceptable salt.
An acid addition salt formed with a specified acid
The pharmaceutically acceptable salt is an acid addition salt formed with an acid selected from hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid, acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid, glucuronic acid, malic acid, gluconic acid, lactic acid, aspartic acid, and malonic acid.
A solution contained within an IV bag
The formulation is provided in a solution contained within an IV bag.
Overall, the claim set focuses on a highly concentrated rifabutin aqueous solution that includes solvent, water, and acid, with concentration between about 50 mg/mL and about 250 mg/mL. The dependent claims narrow the solvent and acid to defined lists, optionally specify rifabutin as a pharmaceutically acceptable salt and an acid addition salt, and restrict the presentation to a solution contained within an IV bag.
Stated Advantages
Enables stable reconstituted solutions that can be diluted without precipitation.
Allows rapid dissolution of rifabutin powder in the presence of the acid-containing solvent.
Documented Applications
Non-oral administration including IV delivery using the concentrated rifabutin aqueous solution contained within an IV bag.
Non-oral administration including inhalation of diluted rifabutin solution.
Treatment methods for bacterial infections are described, including infections associated with M. tuberculosis and MAC (Mycobacterium avium/intracellulare), as well as other pathogens listed in the document.
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